Pathway-specific TNF-mediated metaplasticity in hippocampal area CA1.

Long-term potentiation (LTP) is regulated in part by metaplasticity, the activity-dependent alterations in neural state that coordinate the direction, amplitude, and persistence of future synaptic plasticity. Previously, we documented a heterodendritic metaplasticity effect whereby high-frequency priming stimulation in stratum oriens (SO) of hippocampal CA1 suppressed subsequent LTP in the stratum radiatum (SR). The cytokine tumor necrosis factor (TNF) mediated this heterodendritic metaplasticity in wild-type rodents and in a mouse model of Alzheimer's disease. Here, we investigated whether LTP at other afferent synapses to CA1 pyramidal cells were similarly affected by priming stimulation. We found that priming stimulation in SO inhibited LTP only in SR and not in a second independent pathway in SO, nor in stratum lacunosum moleculare (SLM). Synapses in SR were also more sensitive than SO or SLM to the LTP-inhibiting effects of pharmacological TNF priming. Neither form of priming was sex-specific, while the metaplasticity effects were absent in TNFR1 knock-out mice. Our findings demonstrate an unexpected pathway specificity for the heterodendritic metaplasticity in CA1. That Schaffer collateral/commissural synapses in SR are particularly susceptible to such metaplasticity may reflect an important control of information processing in this pathway in addition to its sensitivity to neuroinflammation under disease conditions.

Tumor Necrosis Factor-α-Mediated Metaplastic Inhibition of LTP Is Constitutively Engaged in an Alzheimer's Disease Model.

LTP, a fundamental mechanism of learning and memory, is a highly regulated process. One form of regulation is metaplasticity (i.e., the activity-dependent and long-lasting changes in neuronal state that orchestrate the direction, magnitude, and persistence of future synaptic plasticity). We have previously described a heterodendritic metaplasticity effect, whereby strong high-frequency priming stimulation in stratum oriens inhibits subsequent LTP in the stratum radiatum of hippocampal area CA1, potentially by engagement of the enmeshed astrocytic network. This effect may occur due to neuron-glia interactions in response to priming stimulation that leads to the release of gliotransmitters. Here we found in male rats that TNFα and associated signal transduction enzymes, but not interleukin-1ß (IL-1ß), were responsible for mediating the metaplasticity effect. Replacing priming stimulation with TNFα incubation reproduced these effects. As TNFα levels are elevated in Alzheimer's disease, we examined whether heterodendritic metaplasticity is dysregulated in a transgenic mouse model of the disease, either before or after amyloid plaque formation. We showed that TNFα and IL-1ß levels were significantly increased in aged but not young transgenic mice. Although control LTP was impaired in the young transgenic mice, it was not TNFα-dependent. In the older transgenic mice, however, LTP was impaired in a way that occluded further reduction by heterosynaptic metaplasticity, whereas LTP was entirely rescued by incubation with a TNFα antibody, but not an IL-1ß antibody. Thus, TNFα mediates a heterodendritic metaplasticity in healthy rodents that becomes constitutively and selectively engaged in a mouse model of Alzheimer's disease.SIGNIFICANCE STATEMENT The proinflammatory cytokine TNFα is known to be capable of inhibiting LTP and is upregulated several-fold in brain tissue, serum, and CSF of Alzheimer's disease (AD) patients. However, the mechanistic roles played by TNFα in plasticity and AD remain poorly understood. Here we show that TNFα and its downstream signaling molecules p38 MAPK, ERK, and JNK contribute fundamentally to a long-range metaplastic inhibition of LTP in rats. Moreover, the impaired LTP in aged APP/PS1 mice is rescued by incubation with a TNFα antibody. Thus, there is an endogenous engagement of the metaplasticity mechanism in this mouse model of AD, supporting the idea that blocking TNFα might be of therapeutic benefit in the disease.

Is plasticity of synapses the mechanism of long-term memory storage?

It has been 70 years since Donald Hebb published his formalized theory of synaptic adaptation during learning. Hebb's seminal work foreshadowed some of the great neuroscientific discoveries of the following decades, including the discovery of long-term potentiation and other lasting forms of synaptic plasticity, and more recently the residence of memories in synaptically connected neuronal assemblies. Our understanding of the processes underlying learning and memory has been dominated by the view that synapses are the principal site of information storage in the brain. This view has received substantial support from research in several model systems, with the vast majority of studies on the topic corroborating a role for synapses in memory storage. Yet, despite the neuroscience community's best efforts, we are still without conclusive proof that memories reside at synapses. Furthermore, an increasing number of non-synaptic mechanisms have emerged that are also capable of acting as memory substrates. In this review, we address the key findings from the synaptic plasticity literature that make these phenomena such attractive memory mechanisms. We then turn our attention to evidence that questions the reliance of memory exclusively on changes at the synapse and attempt to integrate these opposing views.

Predicting the knowledge-recklessness distinction in the human brain.

Criminal convictions require proof that a prohibited act was performed in a statutorily specified mental state. Different legal consequences, including greater punishments, are mandated for those who act in a state of knowledge, compared with a state of recklessness. Existing research, however, suggests people have trouble classifying defendants as knowing, rather than reckless, even when instructed on the relevant legal criteria. We used a machine-learning technique on brain imaging data to predict, with high accuracy, which mental state our participants were in. This predictive ability depended on both the magnitude of the risks and the amount of information about those risks possessed by the participants. Our results provide neural evidence of a detectable difference in the mental state of knowledge in contrast to recklessness and suggest, as a proof of principle, the possibility of inferring from brain data in which legally relevant category a person belongs. Some potential legal implications of this result are discussed.

Do group I metabotropic glutamate receptors mediate LTD?

Synapses undergo significant structural and functional reorganization in response to varying patterns of stimulation. These forms of plasticity are considered fundamental to cognition and neuronal homeostasis. An increasing number of reports highlight the importance of activity-dependent synaptic strengthening (long term potentiation: LTP) for learning. However, the functional significance of activity-dependent weakening of synapses (long term depression: LTD) remains relatively poorly understood. One form of synaptic weakening, induced by group I metabotropic glutamate receptors (mGluRs), has received significant attention from a mechanistic point of view and because of its augmentation in a murine model of Fragile X Syndrome. Yet, studies of this form of plasticity often yield confusing, contradictory results. These conflicting findings are likely attributable to the bulk stimulation and recording techniques often used to study synaptic plasticity (typically involving evoked extracellular recordings, which represent the summed activity of many synapses). Such studies inherently blur the identity of the synapses undergoing change, thus giving the illusion that synapses per se are being modified when in fact this may only be true of a specific subset of synapses. Indeed, studies employing minimal synaptic activation paint a fundamentally different picture of what is commonly called "mGluR-LTD". Here, I review the evidence in favour of group I mGluRs as mediators of various forms of synaptic downregulation and attempt to explain discrepancies in the literature. I argue that, while multiple forms of synaptic weakening may be triggered by these receptors, the canonical form of group I mGluR-mediated depression, mGluR-LTD, is in fact not a depression of basal synaptic responses. Rather, it is a reversal of established LTP and thus a form of depotentiation. Far from being arbitrary, this distinction has significant implications for the role of group I mGluRs in cognition, both in the healthy brain and in pathological conditions. Further, the differential actions of group I mGluRs at naïve and potentiated synapses suggest these receptors signal in a state-dependent manner to regulate various stages of the learning process.

Secreted amyloid precursor protein-alpha can restore novel object location memory and hippocampal LTP in aged rats.

Secreted amyloid precursor protein-α (sAPPα) is a neurotrophic and neuroprotective molecule which can enhance learning and synaptic plasticity. Aging is associated with memory decline and impaired long-term potentiation (LTP). SAPPα therefore has potential as a nootropic agent which could be used to offset age-related cognitive decline. In this study we investigated the effects of sAPPα on spatial memory tasks and LTP in aged and young Long-Evans rats. Two hippocampus-dependent tasks were employed to measure spatial memory that is susceptible to impairments during aging. Aged rats showed a mild deficit in the novel object location task, but memory was significantly enhanced by bilateral intrahippocampal injections of sAPPα. There was no effect on the performance of young animals. In the watermaze task, however, sAPPα did not alleviate age-related decline in spatial memory. In subsequent electrophysiological experiments, LTP was impaired in slices from aged animals, but plasticity was rescued in a concentration-dependent manner by exogenous sAPPα administration. In contrast, LTP was impaired in young animals by sAPPα. Overall, these data support the hypothesis that sAPPα has therapeutic potential as a treatment for age-related cognitive decline.

Parsing the Behavioral and Brain Mechanisms of Third-Party Punishment.

UNLABELLED: The evolved capacity for third-party punishment is considered crucial to the emergence and maintenance of elaborate human social organization and is central to the modern provision of fairness and justice within society. Although it is well established that the mental state of the offender and the severity of the harm he caused are the two primary predictors of punishment decisions, the precise cognitive and brain mechanisms by which these distinct components are evaluated and integrated into a punishment decision are poorly understood. Using fMRI, here we implement a novel experimental design to functionally dissociate the mechanisms underlying evaluation, integration, and decision that were conflated in previous studies of third-party punishment. Behaviorally, the punishment decision is primarily defined by a superadditive interaction between harm and mental state, with subjects weighing the interaction factor more than the single factors of harm and mental state. On a neural level, evaluation of harms engaged brain areas associated with affective and somatosensory processing, whereas mental state evaluation primarily recruited circuitry involved in mentalization. Harm and mental state evaluations are integrated in medial prefrontal and posterior cingulate structures, with the amygdala acting as a pivotal hub of the interaction between harm and mental state. This integrated information is used by the right dorsolateral prefrontal cortex at the time of the decision to assign an appropriate punishment through a distributed coding system. Together, these findings provide a blueprint of the brain mechanisms by which neutral third parties render punishment decisions. SIGNIFICANCE STATEMENT: Punishment undergirds large-scale cooperation and helps dispense criminal justice. Yet it is currently unknown precisely how people assess the mental states of offenders, evaluate the harms they caused, and integrate those two components into a single punishment decision. Using a new design, we isolated these three processes, identifying the distinct brain systems and activities that enable each. Additional findings suggest that the amygdala plays a crucial role in mediating the interaction of mental state and harm information, whereas the dorsolateral prefrontal cortex plays a crucial, final-stage role, both in integrating mental state and harm information and in selecting a suitable punishment amount. These findings deepen our understanding of how punishment decisions are made, which may someday help to improve them.

Corticolimbic gating of emotion-driven punishment.

Determining the appropriate punishment for a norm violation requires consideration of both the perpetrator's state of mind (for example, purposeful or blameless) and the strong emotions elicited by the harm caused by their actions. It has been hypothesized that such affective responses serve as a heuristic that determines appropriate punishment. However, an actor's mental state often trumps the effect of emotions, as unintended harms may go unpunished, regardless of their magnitude. Using fMRI, we found that emotionally graphic descriptions of harmful acts amplify punishment severity, boost amygdala activity and strengthen amygdala connectivity with lateral prefrontal regions involved in punishment decision-making. However, this was only observed when the actor's harm was intentional; when harm was unintended, a temporoparietal-medial-prefrontal circuit suppressed amygdala activity and the effect of graphic descriptions on punishment was abolished. These results reveal the brain mechanisms by which evaluation of a transgressor's mental state gates our emotional urges to punish.

Mechanisms of heterosynaptic metaplasticity.

Synaptic plasticity is fundamental to the neural processes underlying learning and memory. Interestingly, synaptic plasticity itself can be dynamically regulated by prior activity, in a process termed 'metaplasticity', which can be expressed both homosynaptically and heterosynaptically. Here, we focus on heterosynaptic metaplasticity, particularly long-range interactions between synapses spread across dendritic compartments, and review evidence for intracellular versus intercellular signalling pathways leading to this effect. Of particular interest is our previously reported finding that priming stimulation in stratum oriens of area CA1 in the hippocampal slice heterosynaptically inhibits subsequent long-term potentiation and facilitates long-term depression in stratum radiatum. As we have excluded the most likely intracellular signalling pathways that might mediate this long-range heterosynaptic effect, we consider the hypothesis that intercellular communication may be critically involved. This hypothesis is supported by the finding that extracellular ATP hydrolysis, and activation of adenosine A2 receptors are required to induce the metaplastic state. Moreover, delivery of the priming stimulation in stratum oriens elicited astrocytic calcium responses in stratum radiatum. Both the astrocytic responses and the metaplasticity were blocked by gap junction inhibitors. Taken together, these findings support a novel intercellular communication system, possibly involving astrocytes, being required for this type of heterosynaptic metaplasticity.

Neuroscientists in court.

Neuroscientific evidence is increasingly being offered in court cases. Consequently, the legal system needs neuroscientists to act as expert witnesses who can explain the limitations and interpretations of neuroscientific findings so that judges and jurors can make informed and appropriate inferences. The growing role of neuroscientists in court means that neuroscientists should be aware of important differences between the scientific and legal fields, and, especially, how scientific facts can be easily misunderstood by non-scientists, including judges and jurors.

Purinergic receptor- and gap junction-mediated intercellular signalling as a mechanism of heterosynaptic metaplasticity.

Synaptic plasticity is subject to activity-dependent long-term modification (metaplasticity). We have recently described a novel form of heterosynaptic metaplasticity in hippocampal CA1, whereby 'priming' activity at one set of synapses confers a metaplastic state that inhibits subsequent LTP both within and between dendritic compartments. Here, we investigated the roles of purinergic signalling and gap junctions in mediating this long-distance communication between synapses. We found that the heterosynaptic metaplasticity requires the hydrolysis of extracellular ATP to adenosine, and activation of adenosine A2, but not A1 receptors. The metaplasticity was also blocked by the non-selective gap junction blockers carbenoxolone and meclofenamic acid, and by a connexin43-specific mimetic peptide. These results indicate that an intercellular signalling cascade underlies the long-distance communication required for this form of metaplasticity.

Emerging roles of metaplasticity in behaviour and disease.

Since its initial conceptualisation, metaplasticity has come to encompass a wide variety of phenomena and mechanisms, creating the important challenge of understanding how they contribute to network function and behaviour. Here, we present a framework for considering potential roles of metaplasticity across three domains of function. First, metaplasticity appears ideally placed to prepare for subsequent learning by either enhancing learning ability generally or by preparing neuronal networks to encode specific content. Second, metaplasticity can homeostatically regulate synaptic plasticity, and this likely has important behavioural consequences by stabilising synaptic weights while ensuring the ongoing availability of synaptic plasticity. Finally, we discuss emerging evidence that metaplasticity mechanisms may play a role in disease causally and may serve as a potential therapeutic target.

Calcium-dependent but action potential-independent BCM-like metaplasticity in the hippocampus.

The Bienenstock, Cooper and Munro (BCM) computational model, which incorporates a metaplastic sliding threshold for LTP induction, accounts well for experience-dependent changes in synaptic plasticity in the visual cortex. BCM-like metaplasticity over a shorter timescale has also been observed in the hippocampus, thus providing a tractable experimental preparation for testing specific predictions of the model. Here, using extracellular and intracellular electrophysiological recordings from acute rat hippocampal slices, we tested the critical BCM predictions (1) that high levels of synaptic activation will induce a metaplastic state that spreads across dendritic compartments, and (2) that postsynaptic cell-firing is the critical trigger for inducing that state. In support of the first premise, high-frequency priming stimulation inhibited subsequent long-term potentiation and facilitated subsequent long-term depression at synapses quiescent during priming, including those located in a dendritic compartment different to that of the primed pathway. These effects were not dependent on changes in synaptic inhibition or NMDA/metabotropic glutamate receptor function. However, in contrast to the BCM prediction, somatic action potentials during priming were neither necessary nor sufficient to induce the metaplasticity effect. Instead, in broad agreement with derivatives of the BCM model, calcium as released from intracellular stores and triggered by M1 muscarinic acetylcholine receptor activation was critical for altering subsequent synaptic plasticity. These results indicate that synaptic plasticity in stratum radiatum of CA1 can be homeostatically regulated by the cell-wide history of synaptic activity through a calcium-dependent but action potential-independent mechanism.

Evolution and the expression of biases: situational value changes the endowment effect in chimpanzees.

Cognitive and behavioral biases, which are widespread among humans, have recently been demonstrated in other primates, suggesting a common origin. Here we examine whether the expression of one shared bias, the endowment effect, varies as a function of context. We tested whether objects lacking inherent value elicited a stronger endowment effect (or preference for keeping the object) in a context in which the objects had immediate instrumental value for obtaining valuable resources (food). Chimpanzee subjects had opportunities to trade tools when food was not present, visible but unobtainable, and obtainable using the tools. We found that the endowment effect for these tools existed only when they were immediately useful, showing that the effect varies as a function of context-specific utility. Such context-specific variation suggests that the variation seen in some human biases may trace predictably to behaviors that evolved to maximize gains in specific circumstances.

Variables influencing the neural correlates of perceived risk of physical harm.

Many human activities involve a risk of physical harm. However, not much is known about the specific brain regions involved in decision making regarding these risks. To explore the neural correlates of risk perception for physical harms, 19 participants took part in an event-related fMRI study while rating risky activities. The scenarios varied in level of potential harm (e.g., paralysis vs. stubbed toe), likelihood of injury (e.g., 1 chance in 100 vs. 1 chance in 1,000), and format (frequency vs. probability). Networks of brain regions were responsive to different aspects of risk information. Cortical language- processing areas, the middle temporal gyrus, and a region around the bed nucleus of stria terminalis responded more strongly to high- harm conditions. Prefrontal areas, along with subcortical ventral striatum, responded preferentially to high- likelihood conditions. Participants rated identical risks to be greater when information was presented in frequency format rather than probability format. These findings indicate that risk assessments for physical harm engage a broad network of brain regions that are sensitive to the severity of harm, the likelihood of risk, and the framing of risk information.

The neural correlates of third-party punishment.

Legal decision-making in criminal contexts includes two essential functions performed by impartial "third parties:" assessing responsibility and determining an appropriate punishment. To explore the neural underpinnings of these processes, we scanned subjects with fMRI while they determined the appropriate punishment for crimes that varied in perpetrator responsibility and crime severity. Activity within regions linked to affective processing (amygdala, medial prefrontal and posterior cingulate cortex) predicted punishment magnitude for a range of criminal scenarios. By contrast, activity in right dorsolateral prefrontal cortex distinguished between scenarios on the basis of criminal responsibility, suggesting that it plays a key role in third-party punishment. The same prefrontal region has previously been shown to be involved in punishing unfair economic behavior in two-party interactions, raising the possibility that the cognitive processes supporting third-party legal decision-making and second-party economic norm enforcement may be supported by a common neural mechanism in human prefrontal cortex.

Endowment effects in chimpanzees.

Human behavior is not always consistent with standard rational choice predictions. Apparent deviations from rational choice predictions provide a promising arena for the merger of economics and biology [1-6]. Although little is known about the extent to which other species exhibit these seemingly irrational patterns [7-9], similarities across species would suggest a common evolutionary root to the phenomena. The present study investigated whether chimpanzees exhibit an endowment effect, a seemingly paradoxical behavior in which humans tend to value a good they have just come to possess more than they would have only a moment before [10-13]. We show the first evidence that chimpanzees do exhibit an endowment effect, by favoring items they just received more than their preferred items that could be acquired through exchange. Moreover, the effect is stronger for food than for less evolutionarily salient objects, perhaps because of historically greater risks associated with keeping a valuable item versus attempting to exchange it for another [14, 15]. These findings suggest that many seeming deviations from rational choice predictions may be common to humans and chimpanzees and that the evaluation of these through a lens of evolutionary relevance may yield further insights in humans and other species.